Biodegradable compositions having pressure sensitive adhesive properties

ABSTRACT

A composition comprising the reaction product of (a) an isocyanate group-containing component having an average functionality of at least 2; and (b) an active hydrogen group-containing component having an average functionality of at least 2. The composition is biodegradable, a solid at 22° C. and below, and has pressure sensitive adhesive properties at a temperature of 37° C. and relative humidity of 100%. The composition may be used to adhere polymer meshes or films to biological tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.13/296,670 filed on Nov. 156, 2011, which claims priority to U.S.Provisional Application Ser. No. 61/413,546, filed on Nov. 15, 2010, theentire contents of which are hereby incorporated by reference.

TECHNICAL FIELD

This invention relates to adhesives for applications involvingbiological tissue.

BACKGROUND

Pressure sensitive adhesives are tacky materials that adhere to avariety of surfaces upon application of finger or hand pressure. Theytypically can be removed from smooth surfaces without leaving a residue.

The most common types of pressure sensitive adhesives are based uponacrylic polymers and copolymers. The acrylic polymers and copolymers,however, are not well-suited for applications involving hard or softbiological tissues because they generally are not sufficientlybiodegradable and biocompatible for in vivo use. Examples of pressuresensitive adhesives that have been proposed for in vivo use includethose based upon biodegradable polyesters such as polyhydroxyalkanoatesand polyesters derived from polylactic acid.

SUMMARY

A composition is described that includes the reaction product of: (a) anisocyanate group-containing component having an average functionality ofat least 2; and (b) an active hydrogen group-containing component havingan average functionality of at least 2. The composition isbiodegradable, a solid at 22° C. and below, and has pressure sensitiveadhesive properties at a temperature of 37° C. and 100% relativehumidity.

In some embodiments, the ratio of isocyanate groups to active hydrogengroups is about 1:1, resulting in a composition that is essentially freeof unreacted isocyanate groups. Such a composition is notmoisture-curable and is permanently pressure sensitive (i.e. permanentlytacky at 37° C. and 100% relative humidity). In other embodiments, theratio of isocyanate groups to active hydrogen groups is greater than1:1, resulting in a composition that contains unreacted isocyanategroups. This composition is a slow curing, moisture-curable compositionthat has pressure sensitive adhesive properties at 37° C. and 100%relative humidity for a period of time until it fully cures. This periodof time is sufficient to bond articles such as polymer meshes and filmsto biological tissue.

The term “component” refers to single reactants, and blends of differentreactants.

In some embodiments, the isocyanate group-containing component isselected from the group consisting of lysine diisocyanate andderivatives thereof, lysine triisocyanate and derivatives thereof, andcombinations thereof.

In some embodiments, the active hydrogen group-containing component isselected from the group consisting of hydroxyl group-containingreactants, amine group-containing reactants, thiol group-containingreactants, carboxylic acid group-containing reactants, and combinationsthereof. The active hydrogen group-containing component may includemono-, di-, and tri-functional hydrogen group-containing reactants,alone or in combination with each other, with the proviso that theaverage functionality of the component is at least two.

In some embodiments, the active hydrogen group-containing component isselected from the group consisting of polyester polyols, polyetherpolyols, and combinations thereof. The active hydrogen group-containingcomponent can also include a hydroxyalkyl derivative of a C₃-C₁₀hydrocarbon such as trimethylol propane. Other examples of suitableactive hydrogen group-containing components include hydroxyalkyl aminessuch as triethanolamine. Still other examples include glycerol andalkoxylated derivatives thereof.

In some embodiments, the composition further includes a catalyst, atackifier (e.g., abietic acid, sucrose benzoate, and combinationsthereof), a stabilizer, or a combination thereof.

The composition may be prepared by reacting (a) an isocyanategroup-containing component having an average functionality of at least2; and (b) an active hydrogen group-containing component having anaverage functionality of at least 2. In some embodiments the reactionmay be conducted in multiple stages. In the first stage, the isocyanategroup-containing component is reacted with a first active hydrogengroup-containing reactant having a functionality of at least 2 to form aurethane reaction product having unreacted isocyanate groups.Thereafter, the urethane reaction product is reacted with a secondactive hydrogen group-containing reactant.

The compositions may be used to adhere a variety of materials to hard orsoft biological tissue. Examples of representative materials includepolymer mesh and films. The composition may be applied to the biologicaltissue, the mesh or film, or both. Because the compositions havepressure sensitive adhesive properties, it is possible to re-positionthe mesh or film during application.

The details of one or more embodiments of the invention are set forth inthe description below. Other features, objects, and advantages of theinvention will be apparent from the description and from the claims.

DETAILED DESCRIPTION

The composition includes the reaction product of (a) an isocyanategroup-containing component having an average functionality of at least2; and (b) an active hydrogen group-containing component having anaverage functionality of at least 2. The composition is biodegradable, asolid at 22° C. and below, and has pressure sensitive adhesiveproperties at a temperature of 37° C. and 100% relative humidity.

The composition may be permanently tacky or may exhibit pressuresensitive properties for a period of time as the composition slowlycures. The permanently tacky compositions are essentially free ofunreacted isocyanate groups and thus do not moisture-cure. Theslow-curing compositions, in contract, do have free isocyanate groups,enabling them to cure, albeit slowly.

The isocyanate group-containing component has an average isocyanatefunctionality of at least 2, and may be at least 3. The term “average”reflects the fact that the isocyanate group-containing component, asexplained in the Summary, above, can include multiple types ofisocyanates, including isocyanates with different functionalities.Suitable isocyanates include those derived from amino acids and aminoacid derivatives. Specific examples include lysine di-isocyanate (“LDI”)and derivatives thereof (e.g., alkyl esters such as methyl or ethylesters) and lysine tri-isocyanate (“LTI”) and derivatives thereof (e.g.,alkyl esters such as methyl or ethyl esters). Dipeptide derivatives canalso be used. For example, lysine can be combined in a dipeptide withanother amino acid (e.g., valine or glycine).

The active hydrogen group-containing component includes one or moreactive hydrogen group-containing reactants. The component has an averagefunctionality of at least 2. Again, the term “average” reflects the factthat the active hydrogen group-containing component, as explained in theSummary, above, can include multiple types of active hydrogengroup-containing reactants, including reactants with differentfunctionalities. For example, the active hydrogen group-containingcomponent could contain a combination of mono-, di-, and tri-functionalhydrogen group-containing reactants.

Examples of suitable active hydrogen group-containing components includehydroxyl-functional components, amine-functional components,thiol-functional components, carboxylic acid-functional components, andcombinations thereof. In some embodiments, some or all of the functionalgroups may be primary groups. A single reactant may contain more thanone type of active hydrogen group.

The individual members of the active hydrogen-group containingcomponent, including the number and type of active hydrogen groups, areselected based upon the desired rheology and hydrophilicity of thecomposition. In general, the active hydrogen-group containing componentis selected to optimize the hydrophilicity of the composition, and thusits tissue-bonding ability. One class of suitable active hydrogengroup-containing components includes polyester polyols, polyetherpolyols, and combinations thereof. Also suitable are multi-functionalalcohols selected from glycerol, di-glycerol, erythritol,pentaerythritol, xylitol, arabitol, fucitol, ribitol, sorbitol,mannitol, and combinations thereof. Hydroxyalkyl derivatives and estersof any of these alcohols such as ethoxylated pentaerythritol aresuitable as well. Examples of suitable mono-functional alcohols include2-methyl propanol.

Another class of suitable active hydrogen group-containing componentsincludes hydroxyalkyl derivatives of C₃-C₁₀ carboxylic or dicarboxylicacids (e.g., dimethylol propionic acid, dimethylol butyric acid, andcombinations thereof), and hydroxyalkyl derivatives of C₃-C₁₀hydrocarbons (e.g., trimethylol propane).

The active hydrogen group-containing component can also be ahydroxyalkyl amine (e.g., triethanolamine), a di-, tri-, or tetralkyleneglycol, or combination thereof. The active hydrogen group-containingcomponent can include charged groups (e.g., ammonium halides andsulfonates) and uncharged groups (e.g., alkyl groups). Also suitable arehydroxyl-functional compounds selected from saccharides (e.g., glucose,fructose, sucrose, or lactose), oligosaccharides, polysaccharides,esters thereof, and combinations thereof.

The compositions may further contain one or more catalysts, tackifiers,stabilizers, or combinations thereof. Examples of suitable catalystsinclude tertiary amines (e.g., aliphatic tertiary amines) andorganometallic compounds (e.g., bismuth salts and zirconium chelates).Specific examples include 1,4-diazabicyclo[2.2.2]octane (“DABCO”),2,2′-dimorpholine diethyl ether (“DMDEE”), bismuth-2-ethylhexanoate, andcombinations thereof.

The polyurethane polymer is inherently tacky. However, tackifiers may beadded if desired to adjust the tack of the composition. Examples ofuseful tackifiers include abietic acid and sucrose benzoate.

Examples of suitable stabilizers include antioxidants (e.g., BHT andBHA), water scavengers (e.g., acyl and aryl halides, and anhydrides),Bronsted acids, and the like.

The composition may be prepared in either a single stage reaction, inwhich reactants are combined together in a “single pot” reaction, or amulti-stage reaction, in which the reactants are reacted sequentially.For example, in the first stage, the isocyanate may be reacted with oneor more polyfunctional active hydrogen-containing reactants, where theratio of active hydrogen groups to isocyanate groups is less than 1(e.g., between about 0.6 and about 0.85) to create an intermediateurethane product having unreacted isocyanate groups. These isocyanategroups are then reacted with additional active hydrogen reactants(polyfunctional, mono-functional, or a combination thereof). In eithercase, the reaction may be carried out in the presence of the solvents,diluents, and/or stabilizers.

EXAMPLES

Trimethylol propane (TMP), polycaprolactone diols (PCl) with molecularweights of 530 and 2000, dichloromethane (DCM), bismuth neodecanoate,dimethyl sulfoxide (DMSO), dimethylethanolamine (DMEA), 2-methylpropanol (2-MP), and methanesulfonic acid (MSA) were obtained fromAldrich Chemical Co and used as received. Lysine ethyl esterdi-isocyanate (LDI, 99.5%) was received from SAFC (Sheboygan, Wis.) andused without further purification. A bismuth neodecanoate/DMSO solutionwas prepared at 0.1 g/mL concentration prior to starting the pressuresensitive adhesive synthesis.

Example 1

Trimethylol propane and either propylene glycol or polycaprolactone werereacted with lysine diisocyanate. The [OH]/[NCO] ratio ranged from 0.577to 0.754, with higher values leading to higher molecular weightmaterial. The resulting urethane oligomer, having pendent isocyanategroups, was then reacted with a low molecular weight active hydrogengroup-containing reactant (2-methyl propanol, ethanolamine, orN,N-dimethylethanolamine) to “end cap” the remaining isocyanate groupsand create the pressure sensitive adhesive composition.

Example 2

Compositions with pressure sensitive adhesive properties were preparedin a two-stage reaction. The ratio of NCO groups to OH groups in stage 1of the reaction was 1.30. The average PCl molecular weight was ˜640. Ofthe free isocyanate groups present after stage 1 of the reaction, ˜32%were capped, in stage 2, with DMEA, and 21% were capped with 2-MP. Theresulting product after stage 2 thus contained some free isocyanategroups.

Stage 1: 1.4 g of TMP (31.3 mmoles OH), 5.11 g of PCl 530 (19.3 mmolesOH), and 1.61 g PCl 2000 (1.61 mmoles OH) were mixed with 20 mL DCM atreflux until a single phase was achieved. The temperature of the systemwas set to 37° C., after which 108.4 μL of the bismuth solution wasadded with stirring. At this point, 6.75 mL (7.7 g, 68.1 mmoles NCO) ofLDI were added, whereupon the temperature in the flask rose. After thetemperature had cooled back to 37° C., 162.6 μL of the bismuth solutionwere added.

Stage 2: At 90 minutes, 513 μL of DMEA (0.455 g, 5.1 mmoles) and 30 μLof bismuth solution were added. After 30 minutes, 315 μL (0.253 g, 3.4mmoles) of 2-MP were added and the mixture stirred for an additional 3hours. Subsequently, 5 mL of DCM and 343 μL of MSA were added to a 20 mLvial and allowed to stir gently for 10 minutes. This solution was thenadded to the mixture described above. Removal of the DCM under vacuumproduced the composition.

The tensile properties of the composition were measured as follows. Thecomposition (˜0.5 g) was applied to a 2.5×4 cm area of a 10 cm×2.5 cmpiece of polyester surgical mesh (Parietex, Tyco Healthcare), leavingone end free of the composition. The composition was dissolved in DCM,and the mesh immersed in this solution. The DCM was removed undervacuum. The resulting composition was solid, smooth, and non-tacky atroom temperature. Meanwhile, a 2.5 cm×4 cm piece of porcine testmaterial (Brennen Medical I-188) was glued to one end of a stainlesssteel coupon (total length=8 cm) using cyanoacrylate adhesive. Theadhesive-mesh construct was then applied to the porcine material and wasplaced in an incubator at 37° C. and 100% relative humidity for 2 hours.During this time, the composition developed pressure sensitiveproperties, including tack, after which it cured.

The assembly described above was clamped into the grips of a tensiletester (Mark-10) and the ultimate strength was tested at 1 mm/minutecrosshead speed; ultimate strength was typically in the range of 15-20N.

Example 3

The properties of the composition can be varied in a controlled manner.For example, the OH:NCO ratio was varied between 1.2 and 1.6, wherelower values produced compositions with higher elasticity but highersoftening temperatures, and higher values produced compositions withhigher tack at lower temperature, yet reduced elasticity.

Altering the average molecular weight of the PCl was accomplished byvarying the relative amounts of PC1530 and 2000; higher averagemolecular weight increased the softening temperature.

Regarding capping of the isocyanate groups in stage 2 of the reaction,use of relatively more DMEA versus 2-MP produced a more hydrophilicpressure sensitive adhesive. Leaving a fraction of the isocyanate groups“uncapped” after stage 2 produced a composition that that cured slowlyover time at 37C and 100% RH, but which had pressure sensitive adhesiveproperties under these conditions prior to full cure. On the other hand,capping all isocyanate groups in stage 2 produced a composition that waspermanently tacky.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

1. (canceled)
 2. A method of making a composition comprising reacting:(a) an isocyanate group-containing component having an averagefunctionality of at least 2; and (b) an active hydrogen group-containingcomponent having an average functionality of at least 2 to form acomposition that is biodegradable, a solid at 22° C. and below, and thathas pressure sensitive adhesive properties at a temperature of 37° C.and relative humidity of 100%.
 3. A method according to claim 2comprising: (i) reacting the isocyanate group-containing component witha first active hydrogen group-containing reactant having a functionalityof at least 2 to form a urethane reaction product having unreactedisocyanate groups; and (ii) reacting the urethane reaction product witha second active hydrogen group-containing reactant.
 4. A methodaccording to claim 3 wherein the second active hydrogen group-containingreactant comprises a mono-functional active hydrogen group-containingreactant.
 5. A method of adhering a polymer mesh or film to biologicaltissue comprising: (a) applying the composition of claim 2 to thepolymer mesh or film to form a pressure sensitive adhesive-bearing meshor film; and (b) adhering the pressure sensitive adhesive-bearing meshor film to biological tissue through the composition.